Iso-benzmorphan derivatives



2,959,594 ISO-BENZMORPHAN DERI'vATivEs Maxwell Gordon, Elkins Park, and John J. Lafferty, Levittown, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N Drawing. Filed Sept. 22, 1958, Ser. No. 762,208

6 Claims. (Cl. 260294.3)

This invention relates to a novel series of N-substituted iso-benzmorphan derivatives which have pronounced analgetic activity. More specifically, this invention relates to iso-2'-hydroxy-5,9-dimethyl-2-substituted-6,7-benzmorphan derivatives.

The family of isomeric benzmorphans of this invention have pronounced analgetic or pain-relieving activity. These compounds possess this pharmacodynamic activity following oral administration. Furthermore, they are produced by synthetic means more conveniently than are members of the Well-known morphine family of natural analgetics. These compounds also possess considerable ataractic or tranquilizing activity. Additionally, these compounds possess minimal toxicity or addiction potential.

The compounds of this invention are represented by the following strucural formula:

Formula 1 in which R represents hydrogen, methyl or phenylalkyl in which the alkyl chain is from 1 to 4 carbons and is preferably ethyl.

The preferred and advantageous compound of this in vention is iso-2'-hydroxy-5,9-dimethyl-2-(,B-phenethyl)- 6,7-benzmorphan and its acid addition salts. Iso-2'-hydroxy-S,9-dimethyl-6,7-benzmorphan has considerable use as an intermediate as will be apparent from the following description. In addition, this compound has substantial central nervous system activity, particularly analgetic activity. Chemically, these compounds may be designated as iso-2-hydroxy-5,9-dimethyl-2-substituted-6,7-benzmorphans or iso-1,2,3,4,5,6-hexahydro-6,1l-dimethyl-B-substituted-2,6-methano-3-benzazocines. The isomeric series designated herein as iso has been shown to be distinct from the normal series as far as melting points, solubilities and other physical characteristics are concerned. The exact configuration and relationship of the normal and iso series, however, is not precisely known at this time. There is some evidence that the normal series has the 5,9-methyl substituents in the cis or proximal positions. An alternate point of reference for the 9-methyl group is the 2 or N-substituent, toward which the 9- methyl would also be in the cis or proximal positions. The iso series would have the opposite configuration at these positions. The iso compounds can be reliably produced by the methods described hereafter and have distinct physical characteristics as compared with their normal isomers.

The iso-compounds have been found to be several fold more analgetically active compared with the corresponding normal isomer. The iso compounds exist in optical isomers which can be separated by fractional crystallization of the appropriate diastereoisomeric salts, such as atnt 2,959,594 I V Patented Nov. 8, 1960 2 the D-(+)-u-bromocamphor sulfonic acid or d-tartaric acid salts. This invention is concerned with the analgetically active iso series of substituted benzmorphans as described above. The parent and more easily accessible compounds exist as racemic mixtures with iso-configuration. The individual optical isomers thereof are also included in this invention and are included in any general structural formulae or nomenclature used herein.

The iso-benzmorphans are used as bases or acid addition salts of the bases. The salts are those formed by reacting the bases with nontoxic, pharmaceutically acceptable acids such as inorganic acids, for instance, hydrochloric, hydrobromic, sulfuric, phosphoric, or sulfamic acid, or organic acids, for instance, acetic, maleic, ethanedisulfonic, glycolic, salicylic and fumaric acids. The acid addition salts are prepared by reacting the base with either one equivalent of acid or preferably an excess in an organic solvent such as ether or an ethanol-ether mixture. Alternatively, an acid salt of the base, say the hydrochloride, can be reacted with a salt such as the ammonium salt of an organic acid in an aqueous mixture to form an insoluble salt by double decomposition.

The 2-hydroxyl moiety of the compounds of this invention behaves as a normal phenolic hydroxyl in that it can be esterified or etherified with retention of activity. For instance,.the acetate can be formed by using an excess of acetic anhydride under standard reaction conditions. The methyl ether can be formed by reaction with diazomethane. These derivatives often have somewhat less activity than the parent compound but are still very active compounds and are considered part of this invention. As a practical matter, the carbon content of the acyl or alkyl portions of these derivatives shall be a maximum of 7. Other acyl moieties exemplary of those included are the benzoate, propionate, isobutyrate, etc.

The compounds of this invention are prepared by the following synthetic procedure:

CHa

N-CH Cl CHa 3,4-lutidine methiodide is condensed with p-methoxybenzyl magnesium chloride by heating in a solvent in which the reactants are at least partially soluble, preferably ethyl ether. Alternatively, other reactive esters or halides may be used to form the lutidine quaternary salt or halides to form the benzyl Grignard reagent. The resulting dihydro base is hydrogenated catalytically with a palladium catalyst to the tetrahydro base which is then cyclized by heating for prolonged periods in the presence of a cyclizing agent, such as 48% hydrogen bromide solution of phosphoric acid. The resulting mixture of isomers is separated into the normal and iso series by fractional crystallization from ethyl ether. The

HO Mixture of iso and normal ring closure is assumed to take place in the cis positions 3 at the 1,5-bridgeheads, based on stereochemical considerations of similar reactions. Such closure leads to the presumed structures of the iso and normal series previously discussed herebefore.

N-phenylalkyl members of the series are prepared conveniently by demethylating the iso-N-methyl analogue obtained above after O-acetylation in an excess of acetic anhydride. The demthylation takes place by heating with cyanogen bromide in an organic solvent, preferably a halogenated hydrocarbon such as chloroform. The acetyl group is removed by hydrolysis in dilute acid solution. The resulting iso-N-hydrogen-benzmorphan, an important intermediate which is a part of this invention, is then alkylated either with a reactive ester, such as a reactive halide, by heating in dimethylformarnide in the presence of an alkali metal carbonate, for instance sodium or potassium carbonate, or by reacting the base with an acyl chloride or anhydride and reducing the resulting amide, for instance, with lithium aluminum hyiride. The resulting compound is the iso-N-phenylalkyl derivative.

The following examples are representative of the methods of preparation and isolation of the iso-benzmorphan derivatives of this invention. Modifications of these procedures will be obvious to those skilled in the art and these examples are not to be construed as limiting the scope of this invention.

Example 1 A slurry of 25.0 g. of 3,4-lutidine methiodide in 60 ml. of dry ethyl ether is stirred while 400 ml. of a 0.3958 N ethereal solution of p-methoxybenzylmagnesium chloride is added at room temperature. The mixture is stirred for 30 minutes and then decomposed with a solution of 100 ml. of water containing 25 g. of ammonium chloride and 10 ml. of concentrated ammonium hydroxide. The layers are separated. The organic layor is extracted with a solution of 75 ml. of Water and 17 ml. of concentrated hydrochloric acid. The extracts are neutralized and taken into ether. The volatiles are evaporated to leave a light yellow oil, the dehydro base.

The oily residue is then hydrogenated at 17 psi. of hydrogen with 5% palladium-on-barium sulfate in 100 ml. of 2 N hydrochloric acid for six hours. The reaction mixture is filtered, made alkaline and taken through ether to give a light oil, the tetrahydro base.

The oily tetrahydro base (about 10.0 g.) in 150 ml. of 48% hydrobromic acid is heated at 135 C. for 24 hours, and then quenched in an ice slurry. Treating with base and taking through chloroform gives a brown residue of the isomeric mixture of 2'-hydroxy-2,5,9-trimethyl-6,7- benzmorphan.

This residue is triturated with ether, cooled and the resulting slurry filtered. The solid product is dissolved in a minimum of dry ethanol and made acid with ethereal hydrogen chloride. The cooled mixture is filtered to give the hydrochloride salt of the N-methyl-iso-benzmorphan, M.P. 279-282 C., after recrystallization from ethanol. The base melts at 215 C.

The ethereal filtrate is evaporated to give a residue which is neutralized to give the crude normal N-rnethylbenzmorphan isomer, M.P. 229-230 C. The hydrochloride salt of this isomer is formed, M.P. 196-198" C., as a hydrate.

Example 2 A mixture of 10.0 g. of the N-methyl-iso-benzmorphan isolated in Example 1 in 15 ml. of acetic anhydride is heated on the steam bath for about an hour, then quenched in an ice slurry. The mixture is then neutrallZ ed and taken through ether to give the O-acetate denvative, iso-2'-acetoxy-2,5,9-trimethyl-6,7-benzmorphan. The crude acetate (9.5 g.) is reacted with 5.0 g. of cyanogen bromide in 100 ml. of chloroform at reflux for several hours. The volatiles are removed in vacuo to leave a residue which is'refiuxed in m1. of dilute hydrochloric acid for 24 hours. The mixture is cooled, neutralized and taken through chloroform to give the desired desmethyl base as a viscous syrup which crystallized slowly, M.P. 173-175 C. from methanol. The base, 6.5 g., is reacted with 5 .0 g. of phenylacetyl chloride in the presence of an excess of sodium carbonate in water. The mixture is stirred for several hours, diluted with water and taken into ether to give the N- acylated compound. This compound in other (250 ml.) is reacted with an excess of 1.5 M ethereal lithium aluminum hydride at reflux overnight. The reaction mixture is evaporated to dryness, after quenching carefully with water and hydrobromic acid, to give the crude N- phenethyl-iso-benzmorphan hydrobromide salt which is optionally recrystallized from ethanol, M.P. 272-273 C. The hydrobromide salt in the normal series melts at -173 C. The iso base is isolated by neutralizing the hydrobromide salt in an etheralkali mixture, separating and evaporating the organic solvent.

Example 3 A mixture of 300 mg. of 2-hydroxy-2,5,9-trimethyl- 6,7-benzmorphan in 10 ml. of methanol and 5 ml. of ethereal diazomethane solution is stirred in a closed system for several days. Evaporation of the volatiles gives a crude residue of the O-methyl derivative. The hydrochloride salt is prepared by treating the base in acetone with hydrogen chloride gas then diluting with ethyl ether.

Example 4 A mixture of 850 mg. of the iso-desmethyl base prepared in Example 2 in 10 ml. of dimethylformamide with 500 mg. of potassium carbonate and 600 mg. of benzyl chloride is heated at 100 C. for six hours. The reaction mixture is quenched in water and taken through ether to give iso-2-hydroxy-2-benzyl-5,9-dimethyl-6,7- benzmorphan.

This experiment is repeated but using 850 mg. of phenylbutylbromide to give the corresponding iso-2- phenylbutyl derivative.

Example 5 A mixture of 100 mg. of iso-2-hydroxy2,5,9-trimethyl' 6,7-benzmorphan and 2 ml. of isobutyric anhydride are heated on the steam bath for one hour. After quenching in an ice slurry, neutralizing and taking through ether, the isobutyrate ester is recovered.

What is claimed is:

1. A chemical compound of the class consisting of a free base and its nontoxic acid addition salts, the free base being an iso-2'-hydroxy-5,9-dimethyl-2-substituted- 6,7-benzmorphan of the following formula:

in which R is a member selected from the group consisting of hydrogen, methyl and phenylalkyl, said alkyl having from 1 to 4 carbons.

2. Iso 2 hydroxy-5,9-dimethy1-2-(fl-phenethyl)-6,7- benzmorphan.

3. Iso-2'-hydroxy-5,9-dimethyl-6,7-benzmorphan.

4. Iso 2' hydroxy-5,9-dimethyl-2-(fl-phenethyl)-6,7- ben zmorphan hydrobromide.

5. Iso 2' hydroxy-Z,5,9-trimethyl-6,7-benzmorphan hydrochloride.

6. Iso 2' acetoxy-2,5,9-trimethyl-6,7-benzmorphan.

References Cited in the file of this patent May et al.: Journal Organic Chemistry, vol. 20, pp. 257-63; (1955).

Notice of Adverse Decision in Interference In Interference No. 93,057 involving Patent No. 2,959,594, M. Gordon,

and J. J. Lafi'erty, Iso-benzmorphan derivatives, final decision adverse to the vpateiltees was rendered May 14, 1963, ;as to claims 1, 2, 3, 1, 5 and. 6.

[Ofiicial Gazette July 23,1963] 

6. ISO - 2'' - ACETOXY-2,5,9-TRIMETHYL-6,7-BENZMORPHAN. 